This project involves a broad but fundamental study of the physical and chemical processes that can be used to modify the dissolution rates of drug molecules. Through an analysis of the basic mechanisms of the dissolution process, we will generate information and rational strategies to modifying dissolution rates of neutral and ionizable drug molecules. We will explore processes to achieve optimal and controlled time profiles of drugs in the body where rate and extent of dissolution affect their therapeutic value. For some drugs, especially relatively insoluble ones, the rate limiting step to absorption after oral dosing is the dissolution of the compound from the solid phase. For others, dissolution may be too rapid, resulting in spikes in the plasma concentration time profile of the drug in the body and consequently toxicity or other side effects. Also formulation factors such as chemical stability and esthetic appeal factors such as taste may require that the physicochemical properties of the drug be modified. Many of these problems can be solved by preparing poorly water soluble derivatives, such as prodrugs. Of course, in lowering solubility, the dissolution characteristics are changed and so bioavailability compromised. Therefore, ways of manipulating dissolution in a predictable fashion by physical, chemical or biochemical means could solve these types of problems. This grant will attempt to identify the etiology of the poor solubility characteristics of a series of drug molecules by studying their solid and solution thermodynamic properties, their ionization characteristics, etc. and on the basis of this information attempt to alter in a systematic fashion the undesirable properties by using pro durgs or utilization of the ionization characteristics of the molecules. In so doing, we will develop a formal strategy whereby pharmaceutical scientists facing the problem of a poorly dissolving drug molecule can approach this problem using a sound scientific approach rather than some of the empirical attempts that are currently used.